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Metformin and mtor

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https://www.readbyqxmd.com/read/28533436/metformin-synergizes-with-bcl-xl-bcl-2-inhibitor-abt-263-to-induce-apoptosis-specifically-in-p53-defective-cancer-cells
#1
Xinzhe Li, Bo Li, Zhenhong Ni, Peng Zhou, Bin Wang, Jintao He, Haojun Xiong, Fan Yang, Yaran Wu, Xilin Lyu, Yan Zhang, Yijun Zeng, Jiqin Lian, Fengtian He
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28529619/effects-of-prolonged-exposure-to-low-dose-metformin-in-thyroid-cancer-cell-lines
#2
Safar Kheder, Karen Sisley, Sirwan Hadad, Sabapathy P Balasubramanian
Background: Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment. Some sub-types however have a poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). The proposed mechanisms include activation of the Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway and inhibition of the mTOR pathway (which promotes growth and proliferation)...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28525374/the-effect-of-rapamycin-nvp-bez235-aspirin-and-metformin-on-pi3k-akt-mtor-signaling-pathway-of-pik3ca-related-overgrowth-spectrum-pros
#3
Yasuyo Suzuki, Yasushi Enokido, Kenichiro Yamada, Mie Inaba, Kumiko Kuwata, Naoki Hanada, Tsuyoshi Morishita, Seiji Mizuno, Nobuaki Wakamatsu
The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is critical for cellular growth and metabolism. Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS). In this study, we report a Japanese female diagnosed with PROS, who presented with hyperplasia of the lower extremities, macrodactyly, multiple lipomatosis, and sparse hair. Sequencing and mutant allele frequency analysis of PIK3CA from affected tissues revealed that the patient had a heterozygous mosaic mutation (c...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512260/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#4
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512156/effects-of-metformin-on-compensatory-pancreatic-%C3%AE-cell-hyperplasia-in-mice-fed-a-high-fat-diet
#5
Kazuki Tajima, Jun Shirakawa, Tomoko Okuyama, Mayu Kyohara, Shunsuke Yamazaki, Yu Togashi, Yasuo Terauchi
Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-week treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 weeks of HFD-feeding was similar in mice treated with and those treated without metformin...
May 16, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28504725/metformin-ameliorates-core-deficits-in-a-mouse-model-of-fragile-x-syndrome
#6
Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Erika Freemantle, Ruifeng Cao, Vijendra Sharma, Tine Pooters, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Isabelle A Groves, Seyed Mehdi Jafarnejad, Clément Chapat, Elizabeth A McCullagh, Karine Gamache, Karim Nader, Jean-Claude Lacaille, Christos G Gkogkas, Nahum Sonenberg
Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1(-/y) mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.
May 15, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28502303/-effect-of-metformin-on-proliferation-and-apoptosis-of-rat-prolactinoma-mmq-cells-and-related-mechanisms
#7
Kai Jin, Lunliang Ruan, Jiujun Pu, Ailing Zhong, Fuchao Wang, Song Tan, Hua Huang, Jiamin Mou, Gang Yang
Objective To investigate the effect of metformin on the cell proliferation, cell cycle and apoptosis of rat prolactinoma MMQ cells in vitro and related molecular mechanisms. Methods The MMQ cells were treated with 1.25, 2.5, 5, 10, 20 mmol/L metformin for 48 hours. CCK-8 assay was used to assess the cell proliferation ability; flow cytometry was used to analyze the cell cycle distribution and apoptosis; Western blotting was performed to detect the expressions of AMPKα1/2, p-AMPKα, mTOR, p-mTOR, insulin like growth factor 1 receptor (IGF-1R), ERK1/2, p-ERK1/2, AKT, p-AKT, P21, CDK4, cyclin D1, caspase-3, cleaved caspase-3(c-caspase-3), Bcl-2 and BAX...
May 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28498475/targeting-hexokinase-2-inhibition-promotes-radiosensitization-in-hpv16%C3%A2-e7-induced-cervical-cancer-and-suppresses-tumor-growth
#8
Yuan Liu, Tracy Murray-Stewart, Robert A Casero, Ioannis Kagiampakis, Lihua Jin, Jiawen Zhang, Huihui Wang, Qi Che, Huan Tong, Jieqi Ke, Feizhou Jiang, Fangyuan Wang, Xiaoping Wan
In order to improve the sensitivity of cervical cancer cells to irradiation therapy, we targeted hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis, and explore its role in cervical cancer cells. We suppressed HK2 expression and/or function by shRNA and/or metformin and found HK2 inhibition enhanced cells apoptosis with accelerating expression of cleaved PARP and caspase-3. HK2 inhibition also induced much inferior proliferation of cervical cancer cells both in vitro and in vivo with diminishing expression of mTOR, MIB and MGMT...
May 2, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28464864/metformin-produces-growth-inhibitory-effects-in-combination-with-nutlin-3a-on-malignant-mesothelioma-through-a-cross-talk-between-mtor-and-p53-pathways
#9
Kengo Shimazu, Yuji Tada, Takao Morinaga, Masato Shingyoji, Ikuo Sekine, Hideaki Shimada, Kenzo Hiroshima, Takao Namiki, Koichiro Tatsumi, Masatoshi Tagawa
BACKGROUND: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma. METHODS: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses...
May 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28393693/update-on-the-protective-renal-effects-of-metformin-in-diabetic-nephropathy
#10
Andreas Eisenreich, Ulrike Leppert
BACKGROUND: Diabetic nephropathy is one of the most important complications in patients with diabetes mellitus. Main steps crucial for the pathogenesis of diabetic nephropathy involve amongst others the modulation of cell signaling via AMP-activated kinase (AMPK) and mammalian target of rapamycin (mTOR), reactive oxygen generation, and endoplasmic reticulum stress under diabetic or hyperglycemic conditions. These processes mediate increased loss of renal cells, such as podocytes, which consequentially leads to renal damage and loss of renal functions, such as structural integrity and glomerular filtration in diabetic nephropathy...
April 4, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28356082/anti-tumor-effects-of-everolimus-and-metformin-are-complementary-and-glucose-dependent-in-breast-cancer-cells
#11
Gerke Ariaans, Mathilde Jalving, Emma Geertruida Elisabeth de Vries, Steven de Jong
BACKGROUND: Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We investigated the glucose-dependent growth-inhibitory properties of everolimus, metformin and the combination in breast cancer cell lines. METHODS: The breast cancer cell lines MCF-7, MDA-MB-231 and T47D were cultured in media containing 11 mM or 2...
March 29, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28339020/metformin-inhibits-endothelial-progenitor-cell-migration-by-decreasing-matrix-metalloproteinases-mmp-2-and-mmp-9-via-the-ampk-mtor-autophagy-pathway
#12
Wen-Dong Li, Neng-Ping Li, Dan-Dan Song, Jian-Jie Rong, Ai-Min Qian, Xiao-Qiang Li
The aim of the present study was to investigate the effect of metformin on endothelial progenitor cell (EPC) migration and to explore the possible mechanisms. EPCs were treated with metformin, and the migration of EPCs was evaluated by wound healing and Matrigel invasion assays. We also examined the expression levels of of MMP-2 and MMP-9 in EPCs with or without metformin treatment via RT-PCR and western blot analysis, and activities of MMP-2 and MMP-9 in EPCs under different conditions was examined by zymography...
March 21, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28338172/antidiabetic-drug-metformin-mitigates-ovarian-cancer-skov3-cell-growth-by-triggering-g2-m-cell-cycle-arrest-and-inhibition-of-m-tor-pi3k-akt-signaling-pathway
#13
Y-L Fu, Q-H Zhang, X-W Wang, H He
OBJECTIVE: Metformin is one of most extensively prescribed oral hypoglycemic drug and has received increased attention in recent times for its antitumorigenic potential. Many possible mechanisms have been proposed for the ability of metformin to overturn cancer growth in vitro and in vivo. The objective of the present study was to evaluate the anticancer activity of metformin against ovarian SKOV3 cancer cells. MATERIALS AND METHODS: Anticancer activity and IC50 value of metformin were determined by MTT assay...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28332630/pml-nuclear-bodies-contribute-to-the-basal-expression-of-the-mtor-inhibitor-ddit4
#14
Jayme Salsman, Alex Stathakis, Ellen Parker, Dudley Chung, Livia E Anthes, Kara L Koskowich, Sara Lahsaee, Daniel Gaston, Kimberly R Kukurba, Kevin S Smith, Ian C Chute, Daniel Léger, Laura D Frost, Stephen B Montgomery, Stephen M Lewis, Christopher Eskiw, Graham Dellaire
The promyelocytic leukemia (PML) protein is an essential component of PML nuclear bodies (PML NBs) frequently lost in cancer. PML NBs coordinate chromosomal regions via modification of nuclear proteins that in turn may regulate genes in the vicinity of these bodies. However, few PML NB-associated genes have been identified. PML and PML NBs can also regulate mTOR and cell fate decisions in response to cellular stresses. We now demonstrate that PML depletion in U2OS cells or TERT-immortalized normal human diploid fibroblasts results in decreased expression of the mTOR inhibitor DDIT4 (REDD1)...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28319830/anti-proliferative-effect-of-metformin-on-a-feline-injection-site-sarcoma-cell-line-independent-of-mtor-inhibition
#15
J Pierro, C Saba, K McLean, R Williams, E Karpuzoglu, R Prater, K Hoover, R Gogal
Metformin is an oral hypoglycemic drug that has been shown to inhibit cancer cell proliferation via up-regulation of AMPK (AMP-activated protein kinase), and possibly inhibition of mTOR (mammalian target of rapamycin). The purpose of this study was to evaluate the effects of metformin on a feline injection site sarcoma cell line. Cells from a feline injection site sarcoma cell line were treated with metformin at varied concentrations. A dose-dependent decrease in cell viability following metformin treatment was observed, with an IC50 of 8...
March 6, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28298952/insights-for-oxidative-stress-and-mtor-signaling-in-myocardial-ischemia-reperfusion-injury-under-diabetes
#16
REVIEW
Dajun Zhao, Jian Yang, Lifang Yang
Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28274614/metformin-represses-glucose-starvation-induced-autophagic-response-in-microvascular-endothelial-cells-and-promotes-cell-death
#17
Samson Mathews Samuel, Suparna Ghosh, Yasser Majeed, Gnanapragasam Arunachalam, Mohamed M Emara, Hong Ding, Chris R Triggle
Metformin, the most frequently administered drug for the treatment of type 2 diabetes, is being investigated for its potential in the treatment of various types of cancer; however, the cellular basis for this putative anti-cancer action remains controversial. In the current study we examined the effect of metformin on endoplasmic reticulum (ER) stress and autophagy in glucose-starved micro-vascular endothelial cells (MECs). The rationale for our experimental protocol is that in a growing tumor MECs are subjected to hypoxia and nutrient/glucose starvation that results from the reduced supply and relatively high consumption of glucose...
May 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28243322/targeting-metabolic-remodeling-in-triple-negative-breast-cancer-in-a-murine-model
#18
Verónica García-Castillo, Eduardo López-Urrutia, Octavio Villanueva-Sánchez, Miguel Á Ávila-Rodríguez, Alejandro Zentella-Dehesa, Carlo Cortés-González, César López-Camarillo, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Background: Chemotherapy is the backbone of systemic treatment for triple negative breast cancer (TNBC), which is one of the most relevant breast cancers molecular types due to the ability of tumor cells to develop drug resistance, highlighting the urgent need to design newer and safer drug combinations for treatment. In this context, to overcome tumor cell drug resistance, we employed a novel combinatorial treatment including Doxorubicin, Metformin, and Sodium Oxamate (DoxMetOx). Such pharmacological combination targets indispensable hallmarks of cancer-related to aerobic glycolysis and DNA synthesis...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28242651/metformin-suppresses-systemic-autoimmunity-in-roquin-san-san-mice-through-inhibiting-b-cell-differentiation-into-plasma-cells-via-regulation-of-ampk-mtor-stat3
#19
Seon-Yeong Lee, Su-Jin Moon, Eun-Kyung Kim, Hyeon-Beom Seo, Eun-Ji Yang, Hye-Jin Son, Jae-Kyung Kim, Jun-Ki Min, Sung-Hwan Park, Mi-La Cho
Circulating autoantibodies and immune complex deposition are pathological hallmarks of systemic lupus erythematosus (SLE). B cell differentiation into plasma cells (PCs) and some T cell subsets that function as B cell helpers can be therapeutic targets of SLE. Mechanistic target of rapamycin (mTOR) signaling is implicated in the formation of B cells and germinal centers (GCs). We assessed the effect of metformin, which inhibits mTOR, on the development of autoimmunity using Roquin(san/san) mice. Oral administration of metformin inhibited the formation of splenic follicles and inflammation in kidney and liver tissues...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28196954/metformin-and-thyroid-disease
#20
REVIEW
Xianghui Meng, Shuhang Xu, Guofang Chen, Michael Derwahl, Chao Liu
An intriguing area of research in thyroidology is the recently discovered association of insulin resistance with thyroid functional and morphological abnormalities. Individuals with hyperinsulinemia have larger thyroid gland and a higher prevalence of thyroid nodules and cancer. Accordingly, patients treated with metformin have a smaller thyroid volume and a lower risk of incident goiter, thyroid nodule and cancer. Multiple studies in vitro and in vivo have demonstrated that metformin can inhibit the growth of thyroid cells and different types of thyroid cancer cells by affecting the insulin/IGF1 and mTOR pathways...
April 2017: Journal of Endocrinology
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